tbuckley/cabot-search huggingface dataset:
ADENOSINE TO INOSINE RNA EDITING ASSOCIATED TUMOUR MICROENVIRONMENT AS A THERAPEUTIC TARGET IN GLIOBLASTOMA
Authors: Sean Chun-Chang Chen
Journal: Neuro-Oncology (2023)

Abstract AIMS Glioblastoma (GBM) remains incurable because of the high level of intratumor heterogeneity and the poor understanding of its complex genetics. We recently identified adenosine to inosine (A-to-I) RNA editing as a sex- specific prognostic factor in GBM. However, the underlying mechanism remains unclear. We sought to identify RNA editing-associated molecular effectors and assess their prognosis potential. METHOD We analyzed RNA-Seq data of 196 primary IDH wild-type GBMs from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) cohorts. Genome-wide A-to-I RNA editing events were characterized and GBM tumours were split into two subtypes based on RNA editing signatures (high- and low-editing). Differential expression and tumour microenvironment analyses between the two subtypes were performed to identify molecular effectors. Survival impact of these effectors was determined using Cox proportional hazards model. RESULTS Genes more highly expressed in the high-editing subtype were enriched in immune-related pathways, while those more highly expressed in the low-editing subtype were enriched in cell proliferation and stemness path- ways. Consistent with differential expression analysis, high-editing GBMs exhibited higher infiltration levels of macrophages, monocytes and dendritic cells. Intriguingly, increased cell proliferation and elevated infiltration of dendritic cells were associated with poorer survival in men only, whereas enhanced CSF1 (colony stimulating factor 1) response and elevated infiltration of monocytes and Th1 cells conferred poorer survival outcomes in women only. CONCLUSIONS Our study suggests sex-specific impact of A-to-I RNA editing in the pathogenesis of glioblastoma, highlighting the importance of developing sex-specific treatments and opening a new avenue for the design of novel therapeutic targets.
FOCAL MANAGEMENT OF BRAIN METASTASES IN SMALL CELL LUNG CANCER: A SYSTEMATIC REVIEW
Authors: Claudia Dols Wong, Edward Chandy, Giles Critchley, Stephen David Robinson
Journal: Neuro-Oncology (2023)

Abstract AIMS Small cell lung cancer (SCLC) brain metastases (BM) are common at both presentation and relapse. Historically, BM are managed with whole brain radiotherapy (WBRT) +/- chemotherapy. However, WBRT is associated with significant cognitive impairment, and so interest in the focal management of BM (encompassing stereotactic radiosurgery (SRS) and surgery) is increasing. We systematically reviewed the current literature regarding focal BM management. METHOD A systematic literature search of PubMed, Embase, and CENTRAL databases and clinicaltrials.gov was conducted to obtain published articles, abstracts, and ongoing studies regarding focal management of SCLC BM. Exclusion criteria included publication before 2005 and publication in a non-English language. Additional papers were added by reviewing citations of relevant papers. RESULTS Following initial review of 15,420 records, we identified 67 articles eligible for inclusion. 24 were published before 2015 and 44 published 2015-2023. 8 related to surgical BM treatment: case studies (n=6), retrospective cohort studies (n=2). 60 articles were identified regarding SRS: abstracts (n=13), case studies (n=5), retrospective cohort studies (n=14), retrospective case series (n=20), prospective trials (n=8). These papers have been further divided by topic: upfront SRS (n=23), salvage SRS (n=19) and WBRT with SRS boost (n=3). There are several ongoing trials (n=8) investigating outcomes in SRS for SCLC BM, both alone and when compared with WBRT. CONCLUSIONS Focal treatments for SCLC BM are being used more frequently. However, randomised trial evidence for their safety and effectiveness are still pending.
NHS BRAIN CANCER HEALTHCARE AND RESEARCH: DOES IT MATTER WHERE YOU ARE TREATED?
Authors: Nicky Huskens, Camille Goetz, Katie Bushby
Journal: Neuro-Oncology (2023)

Abstract AIMS The Tessa Jowell Centre of Excellence designation initiative recognizes and awards neuro-oncology centres for excellence in patient treatment, care and research. METHOD Twenty-eight NHS centres were assessed through an extensive application form, virtual site visits and patient feedback. Applications were reviewed against a set of standards established through an iterative process in- volving expert specialists in brain cancer treatment and care. RESULTS Many pockets of excellence and innovations were found across the entire patient pathway. Centres demonstrated consistencies in service provision, common challenges threatening service development and sustainability, as well as areas of significant variations. Patients are most likely to experience variations in genetic testing of their tumour samples, access to clinical studies and the extensiveness of nurse and allied health professional- led care and support they receive. To date, 17 centres have been awarded Excellence status and all applicant centres have obtained support through the Tessa Jowell Academy to develop services and innovate. CONCLUSIONS Based on the findings, patients being treated for brain cancer in any UK centre will be able to obtain an effective standard of care, delivered by a motivated team. There are however areas of striking variation, with disparities in the design, quality and extent of the treatment and care pathway. Service development and addressing gaps in treatment and care will require a tailored approach at both a hospital and national level. In 2023/24, a new application round will open for all UK centres to re-apply to be assessed.
AN AUDIT OF STEROID-INDUCED DIABETES IN PRIMARY BRAIN TUMOUR PATIENTS
Authors: Ji Yun Bog, Cressida Lorimer, Juliet Brock, Edward Chandy
Journal: Neuro-Oncology (2023)

Abstract AIMS Dexamethasone is an effective and commonly used treatment in patients with gliomas. However, it can also cause several metabolic side effects, including steroid-induced diabetes mellitus (SIDM), of which prevalence is estimated at 11-56%. We aimed to assess prevalence of SIDM in our local brain tumour population and audited adherence to recently published national guidance for monitoring and management of SIDM. METHOD Retrospective data review of all new primary malignant brain tumour patients seen in clinic over 12 months to assess local prevalence. Patients’ notes audited for 2 months pre- and post-adoption within the department of national guidelines focussing on how to screen and monitor for diabetes when initiating high dose steroids. RESULTS 71 new patients seen over 12 months. 66 patients with high grade and 5 with low grade gliomas. 82% were on steroids at first oncological visit. 14% known diabetic or pre-diabetic. 7% subsequently developed SIDM. 19 patient notes audited over 2 months prior to intervention (Group 1) and 11 post intervention (Group 2). All patients were taking dexamethasone. 40% of Group 1 and 36% of Group 2 had neither HbA1c nor lab glucose checked at baseline. 1 patient in Group 1 developed SIDM. CONCLUSIONS Diabetes mellitus in cancer patients increases risk of infections, cardiovascular comorbidities, and can reduce effcacy of treatment, leading to preventable admissions and decreased survival rates. Prevalence of SIDM in our local population is comparable to published data. Adoption of published guidance improved baseline monitoring but needs to be embedded within acute oncology pathways across the Trust.
AUTOMATIC DETECTION OF FACIAL LOCATIONS TO MEASURE FACIAL ASYMMETRY AFTER PAEDIATRIC RADIOTHERAPY
Authors: Clea Dronne, Helena Durrant, Angela Davey, Edward Henderson, Eliana Vasquez Osorio, Marianne Aznar
Journal: Neuro-Oncology (2023)

Abstract AIMS Children receiving radiotherapy for head and neck tumours, such as Head and Neck Rhabdomyosarcoma (HN- RMS), often experience facial asymmetry later in life. Here, we present a convolutional neural network (CNN) that will enable the automatic detection of facial anatomical landmarks on MR images taken during follow-up examinations. This model will facilitate quantitative tracking of facial asymmetry, thus revealing the centres of growth that are most affected by radiation, with the ultimate goal of defining precise dose tolerance levels. METHOD A dataset of 61 paediatric MRI images was used to train separate models that infer the locations of four facial landmarks. These locations had previously been manually labelled by two independent observers. Before training, the images were normalised and registered to optimise model performance. The model was judged to be of acceptable accuracy if the distances between the observed landmark (gold-standard location) and the location predicted by the trained models were smaller than the inter-observer distances of each facial landmark. RESULTS The model predicted landmarks which were closer to the gold-standard location than the inter-observer locations. In detail: • Optic chiasm: 0.81 ± 0.45 mm (inter-observer 1.49 mm). • Nasion: 0.70 ± 0.62 mm (inter-observer 3.24 mm). • Left Ectoconchion: 1.22 ± 0.44 mm (inter-observer 3.58 mm). • Right Ectoconchion: 0.80 ± 0.82 mm (inter-observer 4.04 mm). CONCLUSIONS This research shows promising potential for a CNN to accurately locate head and neck landmarks in paediatric MRI images. This tool can label craniofacial landmarks in large clinical datasets quicker and more accurately than can be achieved through manual techniques.
A SINGLE CENTRE 10-YEAR EXPERIENCE WITH GAMMA KNIFE STEREOTACTIC RADIOSURGERY FOR CEREBRAL METASTASES
Authors: Vassili Crispi, Dharsshini Reveendran, Paul Hatfield, Ryan Mathew
Journal: Neuro-Oncology (2023)

Abstract AIMS An estimated 20-40% of patients with metastatic cancer will have brain metastases, whose management depends on multiple factors. Stereotactic radiosurgery (SRS) is increasingly preferred to whole brain radio- therapy (WBRT), since it delivers a precise, high-dose of radiation to individual metastases. This study evaluated the 10-year experience of SRS at the Leeds Gamma Knife Centre. METHOD This is a retrospective, observational study of patients undergoing SRS between 2010 and 2020. Data on primary tumour, Karnofsky Performance Status (KPS), previous treatment for brain metastases, intracranial disease burden, oral steroid therapy, and toxicity were recorded. Follow-up was undertaken for a minimum of 6 months with regular MRI brain. RESULTS 3,940 intracranial metastases in 1,113 patients (478 male) were treated with SRS. Lung (48.2%) and breast (15%) were the most common primary tumours. Median survival was 10 months. Using multivariate analysis, primary diagnosis (p&amp;lt;0.001), KPS (p&amp;lt;0.001), number of lesions (p=0.005) and total tumour volume (p=0.012) were the most statistically significant predictors of survival. At follow-up, 375 (33.7%) patients had new brain metastases. Median time to new metastases was 6 months, and 195 (17.5%) patients underwent further SRS with a median time to repeat SRS of 7 months. Side effects following SRS were usually very mild, primarily including short-term fatigue (28.8%). Steroid dose also dropped significantly after SRS(p&amp;lt;0.001). CONCLUSIONS This 10-year analysis of SRS in brain metastases demonstrated a statistically significant association of survival with pre-treatment predictors, including primary diagnosis, KPS, intracranial disease burden. SRS provides minimal side effects with an associated significant decrease in steroid use following treatment.
PATTERNS OF INfiLTRATION AND RELAPSE OF GLIOBLASTOMA INVOLVING THE ANTERIOR TEMPORAL LOBE: IMPLICATIONS FOR RADIATION THERAPY TARGET VOLUME DELINEATION
Authors: Michael Back, Patrick Horsley, Jackie Yim, James Drummond
Journal: Neuro-Oncology (2023)

Abstract AIMS To characterise specific patterns of infiltration and recurrence for IDH-wildtype Glioblastoma (GBMwt) involving the anterior temporal lobe (ATL) METHOD Patients managed for GBMwt involving ATL between 1/2008-12/2020 were identified. Tumour was segmentated on T1-gadolinium-enhanced(T1gd) and T2-weighted(T2) sequences at baseline and initial relapse. Involvement of adjacent normal structures was assessed: superior temporal gyrus (STG), middle temporal gyrus (MTG), medial occipito-temporal gyrus (MOTG), amygdala, and uncus. Abnormalities in para- hippocampal region (PHG) and sub-insular regions were recorded; as well as distant sites of insular cortex, extreme/external/internal capsule, and frontal lobe. Two major neural pathways were also assessed: the uncinate fasciculus-inferior fronto-occipital fasciculus (UF- IFOF) and hippocampal formation (HP-PHG). RESULTS Of 562 patients 53 involved ATL with 47 included for analysis. Median volume at diagnosis on T1gd and T2 was 36cm3(IQR 12-54) and 51cm3(IQR 23-73) respectively. Adjacent sites involved on T1gd were STG/MTG (87%), amygdala (45%), uncus (8%), MOTG (4%). T2 abnormality extended into insular region in 91%, and hippocampal region in 17% patients. The temporal horn was involved in 21% and compressed/displaced in 63% of patients. Forty patients relapsed with relapse-free survival of 11.4 months. Thirty-five (87%) had T1gd relapse involving a neural pathway: UF-IFOF (74%), HP-PHG (14%), combined (9%), optic tract (3%). Twenty relapses (50%) involved distant sites in external capsule or frontal lobe. Although adjacent to ATL, no relapse occurred posterior to temporal horn or along HP-PHG unless evidence of T2 abnormality was present at diagnosis. All 8 relapses involving the HP-PHG, and none of 26 relapses involving UF-IFOF alone, had T2 involvement of HP-PHG at diagnosis. CONCLUSIONS Infiltration and relapse of GBMwt involving ATL correlates with distinct neural pathways.
SIMVASTATIN INHIBITS MEDULLOBLASTOMA CELL MIGRATION VIA TARGETING THE MEVALONATE PATHWAY
Authors: Charley Comer, David Michod, Maria Victoria Niklison-Chirou
Journal: Neuro-Oncology (2023)

Abstract AIMS Medulloblastoma (MB) is the most common malignant paediatric brain tumour. Arising in the cerebellum, MBs consist of four subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3) and Group 4 (G4), each with unique molecular and genetic features and clinical outcomes. G3 and G4 are the most aggressive, with a high tendency to metastasise, but are the least characterized. Current treatment for MB is surgical resection, radiation and chemotherapy, associated with high morbidity and adverse side effects. Therefore, more targeted and less toxic therapies are needed to improve quality of life for survivors. Cancer cells can enhance lipid metabolism through upregulation of the mevalonate pathway (MVP). Aberrant activity of MVP in tumour cells has been widely reported. Previous studies have shown statins can decrease mortality in colorectal, breast and lung cancer patients, and even decrease metastasis of osteosarcoma. Notably, simvastatin can penetrate the blood-brain barrier. This study aims to utilise statins as a potential novel therapy for MB metastasis. METHOD In silico gene expression analysis was performed to evaluate expression of enzymes involved in MVP in MB, validated through immunocytochemistry and RT-PCR in SHH, G3 and G4 cell lines. Further study analysed the anti-cancer and anti-metastatic potential of simvastatin using both 2D and 3D cell culture methods. RESULTS Results show that in 2D and 3D cell culture, simvastatin is capable of decreasing migration of MB cells in vitro. CONCLUSIONS Our work demonstrates that simvastatin has the capacity to decrease MB cell invasion, therefore making it an appealing novel therapy option for MB tumours.
GRAPHENE NANOMATERIAL REPROGRAMMING OF IMMUNE CELLS TO UNLOCK THE EffCACY OF IMMUNOTHERAPY IN GLIOBLASTOMA
Authors: Thomas Kisby, Maria Stylianou, Kostas Kostarelos
Journal: Neuro-Oncology (2023)

Abstract AIMS Immunotherapy has substantiated its promise and achieved striking clinical effcacy in at least a subset of patients in several cancer types. However, in patients with glioblastoma multiforme (GBM), immunotherapies have lacked effcacy as a consequence of the highly immunosuppressive “cold” tumour microenvironment. Small, thin graphene oxide (GO) nanosheets possess notable pharmacokinetic properties in GBM including deep translocation throughout the whole tumour volume and selective internalization by tumour associated macrophages and microglia (TAMMs) following local administration. The current study aimed to investigate whether this selective nanomaterial-TAMM interaction could be exploited to reprogram the immune- microenvironment of GBM. METHOD GO nanosheets were non-covalently complexed with a TLR7/8 agonist to form a stable immunomodulatory nanosystem (imodGO) which was tested in primary macrophages in vitro, and an orthotopic syngeneic GBM model in vivo. RESULTS ImodGO enhanced the polarization of macrophages toward a pro-inflammatory M1-like phenotype in vitro without disrupting their phagocytic or cytokine producing capacity. A single intratumoral administration of the same nanocomplex in an intracranial GL261 model was also effective in increasing M1-like TAMMs (CD86+, MHCII+, TNFα+) while decreasing immunosuppressive M2-like TAMMs (Ym1+, Arg1+) which resulted in a wider reprogramming of the brain tumour immune-microenvironment. Repeat imodGO administration was able to significantly inhibit tumour progression highlighting the therapeutic potential of this nanomaterial enabled immunomodulatory strategy. CONCLUSIONS Based on these results, imodGO has emerged as a novel strategy to ameliorate the immunosuppressive char- acter of GBM. Further work is warranted to assess whether imodGO could enhance the effcacy of systemic immunotherapies used in combination.
LOW-GRADE GLIOMAS IN OLDER PATIENTS: A MATCHED PROPENSITY-SCORING ANALYSIS TO DETERMINE SEIZURE OUTCOMES AND PROGNOSIS
Authors: Jing Xian Lee, Mueez Waqar, Michael Younis, Helen Maye, Matthew Bailey, Pietro D’urso, David Coope, Amir Saam Youshani, Konstantina Karabatsou
Journal: Neuro-Oncology (2023)

Abstract AIMS Low-grade gliomas (LGG) are associated with significant morbidity and age is assumed to be a negative prognostic factor. The aim of this study was to compare outcomes between older patients with LGGs and a matched cohort of younger patients. METHOD Retrospective review of WHO grade II LGGs from 2009-2022. Propensity-score matching (1:3 matching) was used to compare older (≥65 years old) and matched younger controls (&amp;lt;65 years old). The two groups were matched by age, gender, presenting seizures, Karnofsky performance status, location, extent of resection, use of awake neurosurgical monitoring, histology subtype and post-operative chemoradiotherapy. Survival analysis was performed using Kaplan-Meier survival curves and log-rank test. RESULTS 40 patients were included - 10 older and 30 young. The median age was 70.0 and 48.5 years, respectively, with no differences in other demographic variables. Following resection, the older group had a shorter seizure-free period (median 2.5 vs. 10.9 months) and worse 1-year seizure-free rates (25.0% vs. 50.0%). Other outcomes were also worse in the older group including a shorter overall survival (median 95.0 vs. 117.0 months) and shorter progression-free survival (median 24.0 vs. 61.0 months). CONCLUSIONS In this novel study, we present the first matched analysis to evaluate outcomes in older patients with LGGs. We report worse seizure outcomes, overall survival and progression-free survival in these patients. Larger longitudinal multicentre studies will more accurately assess post-operative seizure-control and prognostic outcomes in between these groups.
GLIOBLASTOMA CELL INVASION IS TARGETABLE BY COMBINATION TREATMENT WITH MIGRASTATIC INHIBITORS
Authors: Sally Prior, Jessica Senior, Kayley Jaworska, Eryn Burns, Zara Ahmed, Hayley Butler, Anke Brüning-Richardson
Journal: Neuro-Oncology (2023)

Abstract AIMS One of the hallmarks of cancer is cell migration and invasion, a striking feature of glioblastoma (GBM). The highly migratory potential of tumour cells enables recurrence of GBM tumours leading to poor survival and patient death. We recently characterised a panel of migrastatic inhibitors and reported on the ability of glioma cells to overcome drug activity by employing a mesenchymal to amoeboid migratory switch. Here we demonstrate that targeting different signalling pathways involved in cell migration induces synergistic drug activity of single inhibitors. METHOD The previously described inhibitors CCG-1423 and Rhosin Hydrochloride were used singly or in combination to target cell migration in established glioma cell lines. Characterisation of drug activity was achieved by 2D and 3D migration and invasion assays and cytoskeletal and morphological changes were assessed by immunofluorescence assays. RESULTS When used in single applications, the inhibitors did not have a significant effect on cell migration in 2D and 3D. However, combination treatments led to significantly reduced migration in both 2D and 3D with notable effects on the cytoskeleton as evidenced by changes in focal adhesion dynamics and in actin localisation. Cellular features also changed in response to combination treatment as noted by increase in cell size and adhesion to neighbouring cells. CONCLUSIONS The observed effects are in keeping with targeting two distinct signalling pathways driving cells to either adopt amoeboid or mesenchymal cell migration/invasion mechanisms. We propose that a ‘cocktail’ of migrastatic inhibitors should be included in future experimental designs for consideration as novel, complementary treatment strategies in GBM.
Chemo-immunotherapy by dual-enzyme responsive peptide self-assembling abolish melanoma
Authors: Yuhan Wang, Limin Xie, Xinxin Li, Ling Wang, Zhimou Yang
Journal: Bioactive Materials (2023)

Herein, we designed Comp. 1 to simultaneously respond to two enzymes: alkaline phosphatase and matrix metalloproteinase 2, which is commonly found in highly malignant cancer cell lines containing B16-F10 murine melanoma cells and CT26 murine colon carcinoma cells. We used the regional differences in the expression levels of dual-markers to accurately release immune molecule IND into tumor microenvironment for the activation of anti-tumor related immune effects, while in-situ self-assembly occurs. The dual-enzyme response process can further regulate the peptide precursors' self-assembly in the form of short rod-shaped nanofibers, enabling the delivery of the loaded chemotherapeutic drug HCPT into the cancer cells and further allowing the peptide assemblies to escape from lysosomes and return to cytoplasm in the form of tiny nanoparticles to induce apoptosis of cancer cells. This process does not occur in the single-positive breast cancer cell line MCF-7 or the normal hepatocytes cell line LO2, indicating the selectivity of the cancer cells exhibited using our strategy. In vivo studies revealed that Comp. 1 can effectively cooperate with chemotherapy to enhance the immunotherapy effect and induce immune responses associated with elevated pro-inflammatory cytokines in vivo to inhibit malignant tumors growth. Our dual-enzyme responsive chemo-immunotherapy strategy feasible in anti-tumor treatment, provides a new avenue for regulating peptide self-assembly to adapt to diverse tumor properties and may eventually be used for the development of novel multifunctional anti-tumor nanomedicines.